1. Field of the Invention
The present invention relates to methods for producing a peptide in a high yield utilizing an ionic liquid. In particular, the present invention relates to methods for producing a peptide on an industrial scale.
2. Discussion of the Background
As it would be anticipated that peptides have a great demand as active components of pharmaceutical products, they have conventionally been produced according to a variety of methods. Then there has recently been proposed a method for producing a peptide utilizing an ionic liquid and such a method has accordingly become of major interest. For instance, JP-T-2008-537733 discloses a method for using an ionic liquid to combine with oligo-peptide, an oligo-saccharide or an oligo-nucleotide for improving the solubility in an organic solvent, and for utilizing as a protective group. However, in this method, a protective group and a condensation agent are required in each polymerization reaction.
In Biotechnol. Prog., 2000, 16: 1129-1131, the reaction: Z-Asp+PM→Z-APM is conducted in an ionic liquid (BP6 [1-butyl-3-methyl-imidazolium hexafluoro phosphate)] utilizing an enzyme (Thermolysin). Thus, it is established that an enzymatic reaction can be carried out even in an ionic liquid. The yield of this reaction is high, on the order of 90%, but the reaction should be conducted at considerably low concentrations of reactants. For this reason, the reaction disclosed in this article is considered to be an enzymatic reaction-in an organic solvent in which a solvent is simply substituted.
In addition, JP-A-2008-301829 discloses the synthesis of a peptide in an ionic liquid (4-methyl-N-butyl-pyridinium tetrafluoro borate). The synthesis herein is also considered to be an enzymatic reaction-in an organic solvent in which a solvent is simply substituted, as in Biotechnol. Prog., 2000, 16: 1129-1131. Moreover, in this synthesis, the reaction is carried out at a considerably low concentration, on the order of 20 mM, and the reaction requires the use of a protective group.
Acc. Chem. Res., 2007, 40: 1122-1129 establishes that an amino acid can be converted into its ionic liquid form by combining the amino acid with a residual group of an ionic liquid through an ionic bond. Although the document does not discuss its application, a use for an electrolyte of a fuel cell has initially been investigated.
“Advance in Liquid-Phase Organic Synthesis Using Functional Ionic Liquid as Supports”, Nanjing University of Technology, HU Yi, LI Heng, HUANG He, WEI Ping, Issued on March, 2007, describes a review of the synthesis of polypeptides, oligosaccharides or other organic substances using an ionic liquid and the gist thereof describes that a substrate-ionic liquid is used as an intermediate for such a synthesis. However, there is no specific data.
“Progress on Amino Acid-Ionic Liquid”, Liaoning University, WU Yang, ZHANG Tian-tian, SONG Xi-ming, Issued on March, 2008, discloses an introductory review of an ionic liquid combined with an amino acid. it refers to the applications thereof as a solvent or a catalyst in the near future, although there is not disclosed therein any specific data at all.
However, the methods for synthesizing a peptide utilizing an ionic liquid, which have been proposed until now, provide the peptide in a low yield and neither of them is a method for producing a peptide in an industrial scale.
Thus, there remains a need for improved processes for producing a peptide in a high yield utilizing an ionic liquid.